[go: up one dir, main page]

CN1303069C - Tetrandrine and Tetrandine Compounds, Synthesis and Uses - Google Patents

Tetrandrine and Tetrandine Compounds, Synthesis and Uses Download PDF

Info

Publication number
CN1303069C
CN1303069C CNB038191261A CN03819126A CN1303069C CN 1303069 C CN1303069 C CN 1303069C CN B038191261 A CNB038191261 A CN B038191261A CN 03819126 A CN03819126 A CN 03819126A CN 1303069 C CN1303069 C CN 1303069C
Authority
CN
China
Prior art keywords
ketone
hydrogen
compound
indenes
dimethoxy
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Expired - Fee Related
Application number
CNB038191261A
Other languages
Chinese (zh)
Other versions
CN1675183A (en
Inventor
秦国伟
唐希灿
P·莱塔热
D-H·凯尼亚尔
P·勒纳尔
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Shanghai Institute of Materia Medica of CAS
Laboratoires Servier SAS
Original Assignee
Shanghai Institute of Materia Medica of CAS
Laboratoires Servier SAS
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Shanghai Institute of Materia Medica of CAS, Laboratoires Servier SAS filed Critical Shanghai Institute of Materia Medica of CAS
Publication of CN1675183A publication Critical patent/CN1675183A/en
Application granted granted Critical
Publication of CN1303069C publication Critical patent/CN1303069C/en
Anticipated expiration legal-status Critical
Expired - Fee Related legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/56—Ring systems containing three or more rings
    • C07D209/96—Spiro-condensed ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/56—Ring systems containing three or more rings
    • C07D209/80—[b, c]- or [b, d]-condensed
    • C07D209/82—Carbazoles; Hydrogenated carbazoles
    • C07D209/88—Carbazoles; Hydrogenated carbazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the ring system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
    • C07D217/12—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with radicals, substituted by hetero atoms, attached to carbon atoms of the nitrogen-containing ring
    • C07D217/18—Aralkyl radicals
    • C07D217/20—Aralkyl radicals with oxygen atoms directly attached to the aromatic ring of said aralkyl radical, e.g. papaverine

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Biomedical Technology (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Medicinal Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Psychology (AREA)
  • Hospice & Palliative Care (AREA)
  • Psychiatry (AREA)
  • Epidemiology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
  • Indole Compounds (AREA)

Abstract

本发明涉及青防己碱及其化合物，还涉及式(I)化合物：其中：·R1和R2各自代表氢原子或者一起构成另外的键，·R3代表氢原子或烷氧基，·R5代表氢或氯原子，·R6代表氢原子或烷基、烷基羰基或芳酰基，·R7和R10各自代表烷氧基，·R10代表烷氧基，·R4、R8、R9、R11、R12、R13和R14如说明书所定义。

Figure 03819126

The present invention relates to tetrandrine and its compounds, and also to compounds of formula (I): wherein: · R1 and R2 each represent a hydrogen atom or together form another bond, · R3 represents a hydrogen atom or an alkoxy group, · R5 represents a hydrogen or a chlorine atom, · R6 represents a hydrogen atom or an alkyl group, an alkylcarbonyl group or an aromatic acyl group, · R7 and R10 each represent an alkoxy group, · R10 represents an alkoxy group, · R4 , R8 , R9 , R11 , R12 , R13 and R14 are as defined in the specification.

Figure 03819126

Description

Acutumine and acutumine compound, synthetic and purposes
Yellow parilla (Menispermum dauricum) is a kind of climber of wooden sample, reach more than ten meters, (" national herbal medicine compilation " writes group (Editorial Board) extensively to be distributed in Chinese the north, northeast and east, " national herbal medicine compilation (National Collective Data of ChineseTraditional and Herbal Medicines) ", the People's Health Publisher, first version (Chinese), 1975, p.105).The exsiccant rhizome is called Rhizoma Menispermi (Rhizoma Menispermi), is the part of Chinese medicine, now is embodied in (the Pharmacopoeia of People's Republic of China council, 2000) in the Chinese Pharmacopoeia as analgesic agent and febrifuge by official.
The effective constituent of yellow parilla mainly is alkaloid (crude extract 1 to 2%).Separated and characterized the alkaloid that has various structures in a large number, for example Bisbenzylisoquinolincompounds, the different aporphine of oxidation, aporphine, former aporphine, morphinane or the like.
Purified large number of biological alkali, and studied their pharmacological property.For example, dauricine is the main alkaloid composition of rhizome, has been found that to have cardiovascular system activity and antiinflammatory property.It has been used to treat ARR patient clinically.
Radix Sophorae Tonkinensis Su Lin alkali (dahurisoline) is the alkaloid that another kind has the Bisbenzylisoquinolincompounds structure, show myorelaxant effects (Liu Chang-Xiao etc., " Modern Research andApplication of Chinese Medicinal Plants ", Hong Kong Medical Publisher, first version (English), 2000, p.480).
Acutumine (acutumine) is the less important alkaloid component of rhizome, is found in 1967, has special characteristic (Tomita because of containing the chlorine atom, M. etc., Chemical and PharmaceuticalBulletin (chemistry and pharmacy communique), 1971,19 (4), p.770).We have been found that now acutumine has the cognitive performance that promotes of memory in animal experimental model.
Prolong the aging of population brought by predicted life and cause that the relevant cognitive illnesses of pathologic brain aging aging with normal brain activity or that occur in the process of neurodegenerative disease such as Alzheimer increases greatly.
The most of materials that are used for the treatment of the cognitive illnesses relevant with aging now play a role-directly promote under the situation of acetylcholinesterase depressant (tacrine, E2020 (donepezil)) and cholinergic agonist (nefiracetam) by promoting central cholinergic system, perhaps promote indirectly under the situation of moral function activator (nootropic agents) (piracetam, pramiracetam) and cerebral vasodilator (vinpocetin).
Therefore particularly importantly synthetic novel compound, they can resist with old and feeble relevant cognitive illnesses and/or improve cognitive process.
One aspect of the present invention relates to acutumine
Figure C0381912600151
And/or the acutumine compound is in the purposes of memory in the cognitive illnesses, relates to the synthesizing of new compound that has valuable pharmacological character particularly in same area on the other hand.
The present invention more specifically relates to formula (I) compound:
Figure C0381912600152
Wherein:
R 1And R 2Represent hydrogen atom separately or constitute other key together,
R 3Represent hydrogen atom or alkoxyl group,
R 4Represent hydrogen atom or hydroxyl, alkoxyl group, alkyl-carbonyl oxygen base or aryl carbonyl oxygen base,
R 5Represent hydrogen or halogen atom,
R 6Represent hydrogen atom or alkyl, alkyl-carbonyl or aroyl,
R 7Representation alkoxy,
R 8And R 9Constitute other key together,
Perhaps R 8And R 13Constitute the thioether bridge together, and in this case, R 9And R 10Constitute the oxo base together, R 14Represent the chlorine atom,
R 10Representation alkoxy,
R 11Representation hydroxy or alkoxyl group,
R 12Represent hydrogen atom,
Perhaps R 11And R 12Constitute oxo, oximido or O-alkyl-oximido together,
R 13And R 14Represent hydrogen atom separately or constitute the oxo base together, its condition is that formula (I) compound can not be represented:
-spiral shell [(4S, 5S)-4-hydroxyl-3-methoxyl group-2-cyclopentenes-1-ketone-5:3 (2S)-2-chloro-3aS, 7aS-((2,3)-1-crassitude)-6,7-dimethoxy-1,2,3,3a, 4,7a-six hydrogen-5H-indenes-5-ketone] (acutumine)
-spiral shell [(4S, 5S)-4-ethanoyl-3-methoxyl group-2-cyclopentenes-1-ketone-5:3 (2S)-2-chloro-3aS, 7aS-((2,3)-1-crassitude)-6,7-dimethoxy-1,2,3,3a, 4,7a-six hydrogen-5H-indenes-5-ketone]
-spiral shell [(4S, 5S)-4-ethanoyl-3-methoxyl group-2-cyclopentenes-1-ketone-5:3 (2S)-2-chloro-3aS, 7aS-((2,3)-1-acetyl-pyrrolidine)-6,7-dimethoxy-1,2,3,3a, 4,7a-six hydrogen-5H-indenes-5-ketone]
-spiral shell [(4S, 5S)-4-(benzoyloxy)-3-methoxyl group-2-cyclopentenes-1-ketone-5:3 (2S)-2-chloro-3aS, 7aS-((2,3)-1-crassitude)-6,7-dimethoxy-1,2,3,3a, 4,7a-six hydrogen-5H-indenes-5-ketone]
-spiral shell [(4S, 5S)-4-hydroxyl-pentamethylene-1-ketone-5:3 (2S)-2-chloro-3aS, 7aS-((2,3)-1-crassitude)-6,7-dimethoxy-1,2,3,3a, 4,7a-six hydrogen-5H-indenes-5-phenol]
-spiral shell [(4S, 5S)-4-hydroxyl-3-methoxyl group-2-cyclopentenes-1-ketone-5:3 (2S)-3aS, 7aS-((2,3)-1-crassitude)-6,7-dimethoxy-1,2,3,3a, 4,7a-six hydrogen-5H-indenes-5-ketone]
-spiral shell [(4R, 5S)-4-hydroxyl-3-methoxyl group-2-cyclopentenes-1-ketone-5:3 (2S)-2-chloro-3aS, 7aS-((2,3)-1-crassitude)-6,7-dimethoxy-1,2,3,3a, 4,7a-six hydrogen-5H-indenes-5-ketone]
-spiral shell [(4S, 5S)-4-(benzoyloxy)-3-methoxyl group-2-cyclopentenes-1-ketone-5:3 (2S)-2-chloro-3aS, 7aS-((2,3)-1-benzoyl tetramethyleneimine)-6,7-dimethoxy-1,2,3,3a, 4,7a-six hydrogen-5H-indenes-5-ketone]
-spiral shell [(4S, 5S)-4-ethanoyl-pentamethylene-1-ketone-5:3 (2S)-2-chloro-3aS, 7aS-((2,3)-1-crassitude)-6,7-dimethoxy-1,2,3,3a, 4,7a-six hydrogen-5H-indenes-5-ketone]
-spiral shell [(4S, 5S)-4-hydroxyl-3-methoxyl group-2-cyclopentenes-1-ketone-5:3 (2S)-2-chloro-3aS, 7aS-((2,3)-1H-tetramethyleneimine)-6,7-dimethoxy-1,2,3,3a, 4,7a-six hydrogen-5H-indenes-5-ketone] (N-Noracutumine (acutumidine))
-spiral shell [(4R, 5S)-4-hydroxyl-3-methoxyl group-2-cyclopentenes-1-ketone-5:3 (2S)-2-chloro-3aS, 7aS-((2,3)-1H-tetramethyleneimine)-6,7-dimethoxy-1,2,3,3a, 4,7a-six hydrogen-5H-indenes-5-ketone]
-spiral shell [(5S)-and 2-methoxyl group-2-cyclopentenes-1-ketone-5:3-3aS, 7aS-((2,3)-1H-tetramethyleneimine)-6,7-dimethoxy-1,2,3,3a, 4,7a-six hydrogen-5H-indenes-5-ketone]
-spiral shell [(5S)-and 2-methoxyl group-2-cyclopentenes-1-ketone-5:3-2-chloro-3aS, 7aS-((2,3)-1H-tetramethyleneimine)-6,7-dimethoxy-1,2,3,3a, 4,7a-six hydrogen-5H-indenes-5-ketone],
Be understood that:
-" alkyl " expression contains the alkyl of 1 to 6 carbon atom, and it can be a straight or branched,
-" alkoxyl group " expression contains the alkoxyl group of 1 to 6 carbon atom, and it can be a straight or branched,
-" aryloxy " expression aryl moiety is wherein represented the aryloxy of phenyl or naphthyl,
-" aroyl " expression aryl moiety is wherein represented the aryl carbonyl of phenyl or naphthyl, also relate to its enantiomorph and diastereomer and with the additive salt of pharmaceutically acceptable acid or alkali.
In pharmaceutically acceptable acid, can not add any hydrochloric acid, Hydrogen bromide, sulfuric acid, phosphonic acids, acetate, trifluoroacetic acid, lactic acid, pyruvic acid, propanedioic acid, succsinic acid, pentanedioic acid, fumaric acid, tartrate, toxilic acid, citric acid, xitix, methylsulfonic acid, dextrocamphoric acid, oxalic acid etc. restrictedly mentioned.
In pharmaceutically acceptable alkali, can not add any sodium hydroxide, potassium hydroxide, triethylamine, TERTIARY BUTYL AMINE etc. restrictedly mentioned.
The preferred configuration of formula of the present invention (I) compound is suc as formula shown in (I '):
Figure C0381912600181
Preferred The compounds of this invention is R on the one hand wherein 1And R 2And R on the other hand 8And R 9Constitute formula (I) compound of other key together.
The R of formula of the present invention (I) compound 3, R 7And R 10The preferred meaning of group is a methoxyl group.
R advantageously 4Representation hydroxy, acetoxyl group or benzoyloxy.
R very preferably 5Represent the chlorine atom.
R 6More specifically represent methylidene or ethyl or hydrogen atom.
The present invention preferably relates to wherein R 11And R 12Constitute formula (I) compound of oxo base together.
More particularly, R 13And R 14Represent hydrogen atom separately.
The present invention more advantageously relates to the compound as shown in the formula (I):
-spiral shell [(4S, 5S)-4-(ethoxycarbonyl)-3-methoxyl group-2-cyclopentenes-1-ketone-5:3 (2S)-2-chloro-3aS, 7aS-((2,3)-1-crassitude)-6,7-dimethoxy-1,2,3,3a, 4,7a-six hydrogen-5H-indenes-5-ketone]
-spiral shell [(4S, 5S)-4-hydroxyl-3-methoxyl group-2-cyclopentenes-1-ketone-5:3 (2S)-2-chloro-3aS, 7aS-((2,3)-1-ethyl pyrrolidine)-6,7-dimethoxy-1,2,3,3a, 4,7a-six hydrogen-5H-indenes-5-ketone]
-spiral shell [(4S, 5S)-4-(ethoxycarbonyl)-3-methoxyl group-2-cyclopentenes-1-ketone-5:3 (2S)-2-chloro-3aS, 7aS-((2,3)-1-propionyl tetramethyleneimine)-6,7-dimethoxy-1,2,3,3a, 4,7a-six hydrogen-5H-indenes-5-ketone]
-spiral shell [(4S, 5S)-4-hydroxyl-3-methoxyl group-2-cyclopentenes-1-ketone-5:3 (2S)-2-chloro-3aS, 7aS-((2,3)-1-crassitude)-6,7-dimethoxy-1,2,3,3a, 4,7a-six hydrogen-5H-indenes-5-ketoxime]
-spiral shell [(4S, 5S)-3,4-dimethoxy-2-cyclopentenes-1-ketone-5:3 (2S)-2-chloro-3aS, 7aS-((2,3)-1-crassitude)-6,7-dimethoxy-1,2,3,3a, 4,7a-six hydrogen-5H-indenes-5-ketone]
-spiral shell [(4R, 5S)-4-hydroxyl-3-methoxyl group-2-cyclopentenes-1-ketone-5:3 (2S)-2-chloro-3aS, 7aS-((2,3)-1-crassitude)-6,7-dimethoxy-2,3,3a, 7a-tetrahydrochysene-4H, 5H-indenes-4,5-diketone]
-spiral shell [(5S)-and 3-methoxyl group-2-cyclopentenes-1-ketone-5:3 (2S)-2-chloro-3aS, 7aS-((2,3)-1-crassitude)-6,7-dimethoxy-1,2,3,3a, 4,7a-six hydrogen-5H-indenes-5-ketone]
-spiral shell [(4S, 5S)-4-hydroxyl-2-cyclopentenes-1-ketone-5:3 (2S)-2-chloro-3aS, 7aS-((2,3)-1-crassitude)-6,7-dimethoxy-1,2,3,3a, 4,7a-six hydrogen-5H-indenes-5-phenol]
-spiral shell [(4R, 5S)-4-hydroxyl-3-methoxyl group-2-cyclopentenes-1-ketone-5:3 (2S)-2,4-two chloro-3aS, 7aS-((2,3)-1-crassitude)-7-methoxyl group-8-thia dicyclo [2.2.1]-1,2,3,3a, 4,7a-six hydrogen-5H, 6H-indenes-5,6-diketone].
The enantiomorph of preferred compound of the present invention and diastereomer and constituted integral body of the present invention with the additive salt of pharmaceutically acceptable acid or alkali.
The invention still further relates to the preparation method of formula (I) compound, the method is characterized in that use formula (II) compound (N-Noracutumine) is as raw material:
Formula (II) compound successively with demethylation agent and alkylating agent effect, obtain the special case of formula (I/a) compound-formula (I) compound:
Figure C0381912600201
R ' wherein 3And R ' 10Representation alkoxy separately, R 7Define suc as formula (I),
Formula (I/a) compound can be in reducing medium and formula R 15CHO compound (R wherein 15Represent alkyl) act on, obtain the special case of formula (I/b) compound-formula (I) compound:
Figure C0381912600202
R ' wherein 3, R 7And R ' 10Define R ' as preamble 6Represent alkyl,
Formula (II), (I/a) or (I/b) compound can with formula (R 16CO) 2O compound (R wherein 16Represent alkyl or aryl) act on, obtain the special case of formula (I/c) compound-formula (I) compound:
Figure C0381912600211
R ' wherein 3, R 7And R ' 10Define R as preamble 6Suc as formula (I) define R ' 4Representation hydroxy, alkyl-carbonyl oxygen base or aryl carbonyl oxygen base,
Perhaps formula (II), (I/a), (I/b) or (I/c) compound can with formula E-R 15Compound (R wherein 15Represent alkyl, E represents leavings group such as halogen atom or tosyl group) act on, obtain the special case of formula (I/d) compound-formula (I) compound:
R ' wherein 3, R 6, R 7And R ' 10Define R as preamble 4Define suc as formula (I),
Formula (I/d) compound can with formula R 17ONH 2Compound (R wherein 17Represent hydrogen atom or alkyl) act on, obtain the special case of formula (I/e) compound-formula (I) compound:
R ' wherein 3, R 4, R 6, R 7, R ' 10And R 17Define as preamble,
Perhaps formula (I/d) compound can with SOCl 2/ DMF effect obtains the special case of formula (I/f) compound-formula (I) compound:
R ' wherein 3, R 4, R 6, R 7And R ' 10Define as preamble,
Perhaps formula (I/d) compound can with reductive agent such as LiAlH 4Act on, obtain the special case of formula (I/g) compound-formula (I) compound:
Figure C0381912600223
R wherein 4, R 6, R 7And R ' 10Define symbol as preamble Represent that this key can be singly-bound or two key, perhaps formula (I/d), (I/e), (I/f) or (I/g) compound can be in the presence of AIBN and n-Bu 3The SnH effect obtains the special case of formula (I/h) compound-formula (I) compound:
Figure C0381912600232
R wherein 4, R 6And R 7Define R as preamble 1, R 2, R 3, R 5, R 8, R 9, R 10, R 11, R 12, R 13And R 14Define suc as formula (I),
Formula (I/a) to (I/h) compound constitutes all The compounds of this invention, they can be according to conventional separating technology purifying in addition, be converted into the additive salt of they and pharmaceutically acceptable acid or alkali if necessary, and suitable words are separated into their isomer according to conventional separating technology.
Those skilled in the art can extract the yellow parilla rhizome and acquisition formula (II) compound according to the program of scheme 1.
Scheme 1: the extraction of formula II compound
The compounds of this invention is except novel, they also have the performance that promotes cognitive process, this makes them can be used for treating the cognitive defect relevant with brain aging and neurodegenerative disease, and is for example dull-witted under Alzheimer, Parkinson's disease, Pick's disease (Pick ' s disease), korsakoff's neurosis and frontal lobe and the cortex.
The invention still further relates to pharmaceutical composition, comprise at least a formula (I) compound as activeconstituents and one or more suitable inert non-toxic vehicle.
In addition, the applicant finds that acutumine and/or acutumine compound have the cognitive character that promotes of memory.
Therefore the present invention also relates to acutumine and/or the purposes of acutumine compound in pharmaceutical compositions, this pharmaceutical composition is used for the treatment of the cognitive defect relevant with brain aging and neurodegenerative disease, and is for example dull-witted under Alzheimer, Parkinson's disease, Pick's disease, korsakoff's neurosis and frontal lobe and the cortex.
More particularly, the present invention relates to acutumine and/or the purposes of acutumine compound in pharmaceutical compositions, this pharmaceutical composition is used for the treatment of the cognitive defect relevant with brain aging and neurodegenerative disease, these compounds for example:
-spiral shell [(4S, 5S)-4-hydroxyl-3-methoxyl group-2-cyclopentenes-1-ketone-5:3 (2S)-2-chloro-3aS, 7aS-((2,3)-1-crassitude)-6,7-dimethoxy-1,2,3,3a, 4,7a-six hydrogen-5H-indenes-5-ketone] (acutumine)
-spiral shell [(4S, 5S)-4-ethanoyl-3-methoxyl group-2-cyclopentenes-1-ketone-5:3 (2S)-2-chloro-3aS, 7aS-((2,3)-1-crassitude)-6,7-dimethoxy-1,2,3,3a, 4,7a-six hydrogen-5H-indenes-5-ketone]
-spiral shell [(4S, 5S)-4-ethanoyl-3-methoxyl group-2-cyclopentenes-1-ketone-5:3 (2S)-2-chloro-3aS, 7aS-((2,3)-1-acetyl-pyrrolidine)-6,7-dimethoxy-1,2,3,3a, 4,7a-six hydrogen-5H-indenes-5-ketone]
-spiral shell [(4S, 5S)-4-(benzoyloxy)-3-methoxyl group-2-cyclopentenes-1-ketone-5:3 (2S)-2-chloro-3aS, 7aS-((2,3)-1-crassitude)-6,7-dimethoxy-1,2,3,3a, 4,7a-six hydrogen-5H-indenes-5-ketone]
-spiral shell [(4S, 5S)-4-hydroxyl-pentamethylene-1-ketone-5:3 (2S)-2-chloro-3aS, 7aS-((2,3)-1-crassitude)-6,7-dimethoxy-1,2,3,3a, 4,7a-six hydrogen-5H-indenes-5-phenol]
-spiral shell [(4S, 5S)-4-hydroxyl-3-methoxyl group-2-cyclopentenes-1-ketone-5:3 (2S)-3aS, 7aS-((2,3)-1-crassitude)-6,7-dimethoxy-1,2,3,3a, 4,7a-six hydrogen-5H-indenes-5-ketone]
-spiral shell [(4R, 5S)-4-hydroxyl-3-methoxyl group-2-cyclopentenes-1-ketone-5:3 (2S)-2-chloro-3aS, 7aS-((2,3)-1-crassitude)-6,7-dimethoxy-1,2,3,3a, 4,7a-six hydrogen-5H-indenes-5-ketone]
-spiral shell [(4S, 5S)-4-(benzoyloxy)-3-methoxyl group-2-cyclopentenes-1-ketone-5:3 (2S)-2-chloro-3aS, 7aS-((2,3)-1-benzoyl tetramethyleneimine)-6,7-dimethoxy-1,2,3,3a, 4,7a-six hydrogen-5H-indenes-5-ketone]
-spiral shell [(4S, 5S)-4-ethanoyl-pentamethylene-1-ketone-5:3 (2S)-2-chloro-3aS, 7aS-((2,3)-1-crassitude)-6,7-dimethoxy-1,2,3,3a, 4,7a-six hydrogen-5H-indenes-5-ketone]
-spiral shell [(4S, 5S)-4-hydroxyl-3-methoxyl group-2-cyclopentenes-1-ketone-5:3 (2S)-2-chloro-3aS, 7aS-((2,3)-1H-tetramethyleneimine)-6,7-dimethoxy-1,2,3,3a, 4,7a-six hydrogen-5H-indenes-5-ketone] (N-Noracutumine)
-spiral shell [(4R, 5S)-4-hydroxyl-3-methoxyl group-2-cyclopentenes-1-ketone-5:3 (2S)-2-chloro-3aS, 7aS-((2,3)-1H-tetramethyleneimine)-6,7-dimethoxy-1,2,3,3a, 4,7a-six hydrogen-5H-indenes-5-ketone]
-spiral shell [(5S)-and 2-methoxyl group-2-cyclopentenes-1-ketone-5:3-3aS, 7aS-((2,3)-1H-tetramethyleneimine)-6,7-dimethoxy-1,2,3,3a, 4,7a-six hydrogen-5H-indenes-5-ketone]
-spiral shell [(5S)-and 2-methoxyl group-2-cyclopentenes-1-ketone-5:3-2-chloro-3aS, 7aS-((2,3)-1H-tetramethyleneimine)-6,7-dimethoxy-1,2,3,3a, 4,7a-six hydrogen-5H-indenes-5-ketone].
Favourable aspect of the present invention relates to the purposes of acutumine in pharmaceutical compositions, and this pharmaceutical composition is used for the treatment of the cognitive defect relevant with brain aging and neurodegenerative disease.
Another particularly advantageous aspect of the present invention relates to the purposes of following compounds in pharmaceutical compositions, and this pharmaceutical composition is used for the treatment of the cognitive defect relevant with brain aging and neurodegenerative disease: spiral shell [(4S, 5S)-4-hydroxyl-3-methoxyl group-2-cyclopentenes-1-ketone-5:3 (2S)-2-chloro-3aS; 7aS-(2,3)-1-crassitude)-6,7-dimethoxy-1; 2,3,3a; 4,7a-six hydrogen-5H-indenes-5-ketone]; spiral shell [(4S, 5S)-4-ethanoyl-3-methoxyl group-2-cyclopentenes-1-ketone-5:3 (2S)-2-chloro-3aS; 7aS-((2,3)-1-crassitude)-6,7-dimethoxy-1; 2,3,3a; 4,7a-six hydrogen-5H-indenes-5-ketone]; spiral shell [(4S, 5S)-4-ethanoyl-3-methoxyl group-2-cyclopentenes-1-ketone-5:3 (2S)-2-chloro-3aS; 7aS-((2,3)-1-acetyl-pyrrolidine)-6,7-dimethoxy-1; 2,3,3a; 4,7a-six hydrogen-5H-indenes-5-ketone]; spiral shell [(4S, 5S)-4-(benzoyloxy)-3-methoxyl group-2-cyclopentenes-1-ketone-5:3 (2S)-2-chloro-3aS; 7aS-((2,3)-1-crassitude)-6,7-dimethoxy-1; 2,3,3a; 4,7a-six hydrogen-5H-indenes-5-ketone]; spiral shell [(4S, 5S)-4-hydroxyl-pentamethylene-1-ketone-5:3 (2S)-2-chloro-3aS; 7aS-((2,3)-1-crassitude)-6,7-dimethoxy-1; 2,3,3a; 4,7a-six hydrogen-5H-indenes-5-phenol]; spiral shell [(4S, 5S)-4-hydroxyl-3-methoxyl group-2-cyclopentenes-1-ketone-5:3 (2S)-3aS; 7aS-((2,3)-1-crassitude)-6,7-dimethoxy-1; 2; 3,3a, 4; 7a-six hydrogen-5H-indenes-5-ketone]; spiral shell [(4R; 5S)-and 4-hydroxyl-3-methoxyl group-2-cyclopentenes-1-ketone-5:3 (2S)-2-chloro-3aS, 7aS-((2,3)-1-crassitude)-6; 7-dimethoxy-1; 2,3,3a; 4; 7a-six hydrogen-5H-indenes-5-ketone]; spiral shell [(4S, 5S)-4-(benzoyloxy)-3-methoxyl group-2-cyclopentenes-1-ketone-5:3 (2S)-2-chloro-3aS, 7aS-((2; 3)-and 1-benzoyl tetramethyleneimine)-6; 7-dimethoxy-1,2,3; 3a; 4,7a-six hydrogen-5H-indenes-5-ketone]; spiral shell [(4S, 5S)-4-ethanoyl-pentamethylene-1-ketone-5:3 (2S)-2-chloro-3aS; 7aS-((2; 3)-and the 1-crassitude)-6,7-dimethoxy-1,2; 3; 3a, 4,7a-six hydrogen-5H-indenes-5-ketone]; spiral shell [(4S; 5S)-4-hydroxyl-3-methoxyl group-2-cyclopentenes-1-ketone-5:3 (2S)-2-chloro-3aS; 7aS-((2,3)-1H-tetramethyleneimine)-6,7-dimethoxy-1; 2; 3,3a, 4; 7a-six hydrogen-5H-indenes-5-ketone] (N-Noracutumine); spiral shell [(4R; 5S)-and 4-hydroxyl-3-methoxyl group-2-cyclopentenes-1-ketone-5:3 (2S)-2-chloro-3aS, 7aS-((2,3)-1H-tetramethyleneimine)-6; 7-dimethoxy-1; 2,3,3a; 4; 7a-six hydrogen-5H-indenes-5-ketone]; spiral shell [(5S)-and 2-methoxyl group-2-cyclopentenes-1-ketone-5:3-3aS, 7aS-((2,3)-1H-tetramethyleneimine)-6; 7-dimethoxy-1; 2,3,3a; 4; 7a-six hydrogen-5H-indenes-5-ketone] and spiral shell [(5S)-and 2-methoxyl group-2-cyclopentenes-1-ketone-5:3-2-chloro-3aS, 7aS-((2,3)-1H-tetramethyleneimine)-6; 7-dimethoxy-1; 2,3,3a; 4,7a-six hydrogen-5H-indenes-5-ketone].
The invention still further relates to pharmaceutical composition, comprise acutumine or its compound and one or more pharmaceutically acceptable vehicle, this pharmaceutical composition is used for the treatment of the cognitive defect relevant with brain aging and neurodegenerative disease, and is for example dull-witted under Alzheimer, Parkinson's disease, Pick's disease, korsakoff's neurosis and frontal lobe and the cortex.
In pharmaceutical composition according to the present invention, can more particularly mention those that are suitable for oral, parenteral (intravenously or subcutaneous) or nose administration, formulation is tablet or dragee, Sublingual tablet, gelatine capsule agent, lozenge, suppository, creme, ointment, skin gel agent, injectable formulation, drinkable suspension agent etc.
Useful dosage can be different because of the character of disease and severity, route of administration and patient's age and body weight.The dosage of every day does not wait from 0.01mg to 1g, in single or divided doses.
The following example is set forth the present invention but is never limited it.
Embodiment 1: spiral shell [(4S, 5S)-4-(ethoxycarbonyl)-3-methoxyl group-2-cyclopentenes-1-ketone-5:3 (2S)-2-chloro-3aS, 7aS-((2,3)-1-crassitude)-6,7-dimethoxy-1,2,3,3a, 4,7a-six hydrogen-5H-indenes-5-ketone]
Figure C0381912600281
Steps A: spiral shell [(4S, 5S)-4-hydroxyl-3-methoxyl group-2-cyclopentenes-1-ketone-5:3 (2S)-2-chloro-3aS, 7aS-((2,3)-1-crassitude)-6,7-dimethoxy-1,2,3,3a, 4,7a-six hydrogen-5H-indenes-5-ketone]
1g formula (II) compound is dissolved in HCOOH (10ml), 40-50 ℃ down with 10ml formaldehyde stirring 4 hours.Then with reaction mixture NH 4OH transfers to alkalescence, is 8-9 until pH.Leach the white precipitate that is generated, use K then 2CO 3Drying obtains title compound.
Step B: spiral shell [(4S, 5S)-4-(ethoxycarbonyl)-3-methoxyl group-2-cyclopentenes-1-ketone-5:3 (2S)-2-chloro-3aS, 7aS-((2,3)-1-crassitude)-6,7-dimethoxy-1,2,3,3a, 4,7a-six hydrogen-5H-indenes-5-ketone]
1g steps A gained compound is dissolved in CHCl 3With DMF.Drip the 2ml propionic anhydride then, reaction mixture is stirred spend the night.Add saturated NaHCO then 3Solution is 8-9 until pH, reaction mixture CHCl 3Extraction.After evaporation removed and desolvates, the gained resistates was through silica gel chromatography purifying (CHCl 3: Me 2CO/20: 11), obtain title compound.
Fusing point: 156-158 ℃
Elemental microanalysis:
C H N
Calculated value %:58.21 6.22 3.09
Measured value %:58.00 6.27 3.03
Embodiment 2: spiral shell [(4S, 5S)-4-hydroxyl-3-methoxyl group-2-cyclopentenes-1-ketone-5:3 (2S)-2-chloro-3aS, 7aS-((2,3)-1-ethyl pyrrolidine)-6,7-dimethoxy-1,2,3,3a, 4,7a-six hydrogen-5H-indenes-5-ketone]
50mg formula (II) compound is dissolved in HCOOH (0.5ml), 40-50 ℃ down with 0.5ml acetaldehyde stirring 6 hours.Then with reaction mixture NH 4OH transfers to alkalescence, is 8-9 until pH, mixture CHCl 3Extraction.After evaporation removed and desolvates, the gained resistates was through silica gel chromatography purifying (CHCl 3: Me 2CO/2: 1), obtain title compound.
Fusing point: 156-158 ℃
Elemental microanalysis:
C H N
Calculated value %:58.32 6.31 3.40
Measured value %:57.98 6.31 3.09
Embodiment 3: spiral shell [(4S, 5S)-4-(ethoxycarbonyl)-3-methoxyl group-2-cyclopentenes-1-ketone-5:3 (2S)-2-chloro-3a S, 7aS-((2,3)-1-propionyl tetramethyleneimine)-6,7-dimethoxy-1,2,3,3a, 4,7a-six hydrogen-5H-indenes-5-ketone]
1g formula (II) compound is dissolved in N, N-Dimethylamino pyridine and 2ml CHCl 3Drip the 2ml diacetyl oxide then, reaction mixture is stirred at ambient temperature spend the night.Add saturated NaHCO then 3Solution is 8-9 until pH, reaction mixture CHCl 3Extraction.After evaporation removed and desolvates, the gained resistates was through silica gel chromatography purifying (CHCl 3: Me 2CO/20: 11), obtain title compound.
Fusing point: 166-168 ℃
Elemental microanalysis:
C H N
Calculated value %:58.12 6.09 2.82
Measured value %:57.55 6.03 2.72
Embodiment 4: spiral shell [(4S, 5S)-4-hydroxyl-3-methoxyl group-2-cyclopentenes-1-ketone-5:3 (2S)-2-chloro-3aS, 7aS-((2,3)-1-crassitude)-6,7-dimethoxy-1,2,3,3a, 4,7a-six hydrogen-5H-indenes-5-ketoxime]
Under 70-80 ℃, 1g embodiment 1 steps A gained compound was stirred 4 hours with the 1g azanol in 15ml ethanol.Add saturated NaHCO then 3Solution is 8-9 until pH, reaction mixture CHCl 3Extraction.After evaporation removed and desolvates, the gained resistates was through silica gel chromatography purifying (CHCl 3: Me 2CO/3: 1), obtain the title compound of white solid form.
Fusing point: 211-213 ℃
Elemental microanalysis:
C H N
Calculated value %:55.27 6.10 6.79
Measured value %:55.17 5.79 7.46
Embodiment 5: spiral shell [(4S, 5S)-3,4-dimethoxy-2-cyclopentenes-1-ketone-5:3 (2S)-2-chloro-3aS, 7aS-((2,3)-1-crassitude)-6,7-dimethoxy-1,2,3,3a, 4,7a-six hydrogen-5H-indenes-5-ketone]
Embodiment 1 steps A gained compound (200mg) is dissolved in DMSO, at ambient temperature with 100mg NaOH and 1ml CH 3I stirred 20 minutes.Then reaction mixture is diluted with 5ml water, use CHCl again 3Dilution.After extraction and evaporation removed and desolvate, the gained resistates was through silica gel chromatography purifying (CHCl 3: MeOH/20: 1), obtain the white needles thing of title compound.
Fusing point: 165-167 ℃
Elemental microanalysis:
C H N
Calculated value %:57.32 6.36 3.40
Measured value %:57.18 6.38 3.86
Embodiment 6: spiral shell [(4R, 5S)-4-hydroxyl-3-methoxyl group-2-cyclopentenes-1-ketone-5:3 (2S)-2-chloro-3aS, 7aS-((2,3)-1-crassitude)-6,7-dimethoxy-2,3,3a, 7a-tetrahydrochysene-4H, 5H-indenes-4,5-diketone]
Embodiment 1 steps A gained compound (30mg) is dissolved in SOCl 2, 85 ℃ down with DMF (catalyzer) stirring 30 minutes.Crude product mixture is through silica gel chromatography purifying (CHCl 3: Et 2O/10: 1), obtain title compound.
Fusing point: 152-154 ℃
Embodiment 7: spiral shell [(5S)-and 3-methoxyl group-2-cyclopentenes-1-ketone-5:3 (2S)-2-chloro-3aS, 7aS-((2,3)-1-crassitude)-6,7-dimethoxy-1,2,3,3a, 4,7a-six hydrogen-5H-indenes-5-ketone]
From yellow parilla rhizome gained ethanol extract, be separated to title compound by silica gel chromatography.
Fusing point: 174-176 ℃
Embodiment 8: spiral shell [(4S, 5S)-4-hydroxyl-2-cyclopentenes-1-ketone-5:3 (2S)-2-chloro-3aS, 7aS-((2,3)-1-crassitude)-6,7-dimethoxy-1,2,3,3a, 4,7a-six hydrogen-5H-indenes-5-phenol]
Embodiment 1 steps A gained compound (50mg) is dissolved in THF (15ml), at ambient temperature with LiAlH 4Stirred 2 hours.With the crude product mixture dilute with water, use CHCl 3The silica gel chromatography purifying is passed through in extraction then, obtains title compound.
Embodiment 9: spiral shell [(4R, 5S)-4-hydroxyl-3-methoxyl group-2-cyclopentenes-1-ketone-5:3 (2S)-2,4-two chloro-3aS, 7aS-((2,3)-the 1-crassitude)-7-methoxyl group-8-thia dicyclo [2.2.1]-1,2,3,3a, 4,7a-six hydrogen-5H, 6H-indenes-5,6-diketone]
Program is with embodiment 6 (generating two kinds of compounds (embodiment 6 and 9)) in the process of same reaction sequence.
Fusing point: 214-216 ℃
The pharmaceutical research of The compounds of this invention
Embodiment A: studies on acute toxicity
Evaluation is to 8 the every group mouse (acute toxicities behind 26 ± 2g) oral administrations.In the back first day process of processing, regularly observe animal, observe later every day and once reached for two weeks.Estimate LD 50(dosage that causes 50% animal dead) proves the hypotoxicity of The compounds of this invention.
Embodiment B: mouse Morris water maze test
Utilize mouse Morris water maze test (Morris etc., Nature (nature), 1986,319,774-776) estimate the anti-amnesia of The compounds of this invention, with Scopolamine as forgeing agent.Use female or male Kumming kind mouse (18-24g, Shanghai Experimental Animal Center).Mouse is placed on water maze (on 80 * 50 * 20cm), trains them to find platform.One day custom is after the phase, and every mouse is accepted 3 training and reach seven days every day.The training mouse reaches the standard that found platform and enter mistake＜2 of dead end in 20 seconds.In case mouse is satisfied this standard, reduce training to once a day, all satisfy this standard until all mouse.With trained mouse random packet.Compound to be studied is dissolved in distilled water, by oral route administration in 40 minutes before the behavior test.Preceding 30 minutes of test injection Scopolamine (5mg/kg, i.p.).The time of the number of times of misregistration and arrival platform.Data with on average+/-s.e.m. represents.Utilize ANOVA to carry out statistical analysis, carry out the DuncanShi multiple range test then.
The result proves that The compounds of this invention can descend with the memory of dose-dependently mode (20-100mg/kg) opposing Scopolamine inductive in mouse Morris water maze test, this illustrates that this compounds has the anti-performance of forgeing.
For example, with the compound of the Orally administered embodiment 1 of 60mg/kg, animal arrived platform in 18 seconds, and control animals arrived platform in 43 seconds.
Embodiment C: the social recognition of Wistar rat
The social recognition test was described (J.Comp.Physiol., 1982,96 in nineteen eighty-two by THOR and HOLLOWAY at first, 1000-1006), subsequently by different authors (DANTZER etc., Psychopharmacology (psychopharmacology), 1987,91,363-368; PERIO etc., Psychopharmacology (psychopharmacology), 1989,97,262-268) proposition is used to study the cognitive effect of memory of new compound.This test is based on the natural tendency of expressing naturally and forgeing of rat scent-memorizing, by adult rat to childhood homozoic understanding estimate memory.Get rat childhood (21 days) at random, in the cage of feeding adult rat, placed 5 minutes.By video unit, the experimenter observes the social recognition behavior of adult rat, measures total duration.Take out rat childhood then in the adult rat cage, the cage that is placed on oneself is interior until introducing for the second time.Adult rat is given test compound, contact rat childhood (5 minutes) after 2 hours once more.And then observe the social recognition behavior, measure the time length.Evaluation criteria is the poor (T of 2 experience " understanding " times 2-T 1), show with stopwatch.
The gained result shows, the dosage for 3 to 30mg/kg, difference (T 2-T 1) be (20) second to (45) second, this shows The compounds of this invention memory greatly.
Demonstrate difference (T when for example, the compound of embodiment 4 is used with 20mg/kg 2-T 1) be-45 seconds.
The object understanding of embodiment D:Wistar rat
The test of the object of Wistar rat understanding at first by ENNACEUR and DELACOUR exploitation (Behav.Brain Res. (behavior is studied with brain), 1988,31,47-59).This test is sought and visited activity based on animal spontaneous, has the feature of accidental memory in the mankind.This memory test is to old and feeble (SCALI etc., Eur.J.Pharmacol. (European pharmacology magazine), 1997,325,173-180) with cholinergic function obstacle (BARTOLINI etc., Pharm.Biochem.Behav. (pharmacy, biochemical and behavior), 1996,53 (2), be responsive 277-283), based on the difference of seeking and visiting-one of 2 quite proximate objects of shape is familiar with, another is new.Before the test, make animal conform (cover that does not have object).In the fs, rat is placed on (3 minutes) in the cover, 2 identical objects are wherein arranged.Measurement is sought and visited the time length each object.Subordinate phase after 24 hours (3 minutes) replaces one of 2 objects with new object.Measurement is sought and visited the time length each object.Evaluation criteria be in the subordinate phase process to new object and difference δ to time of seeking and visiting of familiar objects, show with stopwatch.Sought and visited familiar objects and new object with the control animal of vehicle treated in identical mode by the IP approach in 30 minutes in advance before each stage, the object of introducing has previously been forgotten in this explanation.Preferentially seek and visit new object with the animal that promotes the compound treatment that memory is cognitive, the object introduced is previously also remembered in this explanation.
The gained result shows, the dosage for 3 to 30mg/kg, and value of delta is 5 to 10 seconds, this shows The compounds of this invention memory greatly.
Demonstrating the δ value when for example, the compound of embodiment 4 is used with 10mg/kg is 8 seconds.
Embodiment E: pharmaceutical composition
Prepare 1000 tablets of tablets prescription of (every contains the 10mg activeconstituents):
Spiral shell [(4S, 5S)-4-hydroxyl-3-methoxyl group-2-cyclopentenes-1-ketone-5:3 (2S)-2-chloro-3aS, 7aS-((2,3)-and the 1-crassitude)-6,7-dimethoxy-1,2,3,3a, 4,7a-six hydrogen-5H-indenes-5-ketoxime] (embodiment 4) ... the 10g hydroxypropylcellulose ... the 2g wheat starch ... the 10g lactose ... the 100g Magnesium Stearate ... the 3g talcum ... 3g

Claims (24)

1. formula (I) compound:
Wherein:
R 1And R 2Represent hydrogen atom separately or constitute other key together,
R 3Represent hydrogen atom or alkoxyl group,
R 4Represent hydrogen atom or hydroxyl, alkoxyl group, alkyl-carbonyl oxygen base or aryl carbonyl oxygen base,
R 5Represent hydrogen or halogen atom,
R 6Represent hydrogen atom or alkyl, alkyl-carbonyl or aroyl,
R 7Representation alkoxy,
R 8And R 9Constitute other key together,
Perhaps R 8And R 13Constitute the thioether bridge together, and in this case, R 9And R 10Constitute the oxo base together, R 14Represent the chlorine atom,
R 10Representation alkoxy,
R 11Representation hydroxy or alkoxyl group,
R 12Represent hydrogen atom,
Perhaps R 11And R 12Constitute oxo, oximido or O-alkyl-oximido together,
R 13And R 14Represent hydrogen atom separately or constitute the oxo base together, its condition is that formula (I) compound can not be represented:
-spiral shell [(4S, 5S)-4-hydroxyl-3-methoxyl group-2-cyclopentenes-1-ketone-5:3 (2S)-2-chloro-3aS, 7aS-((2,3)-1-crassitude)-6,7-dimethoxy-1,2,3,3a, 4,7a-six hydrogen-5H-indenes-5-ketone] (acutumine)
-spiral shell [(4S, 5S)-4-ethanoyl-3-methoxyl group-2-cyclopentenes-1-ketone-5:3 (2S)-2-chloro-3aS, 7aS-((2,3)-1-crassitude)-6,7-dimethoxy-1,2,3,3a, 4,7a-six hydrogen-5H-indenes-5-ketone]
-spiral shell [(4S, 5S)-4-ethanoyl-3-methoxyl group-2-cyclopentenes-1-ketone-5:3 (2S)-2-chloro-3aS, 7aS-((2,3)-1-acetyl-pyrrolidine)-6,7-dimethoxy-1,2,3,3a, 4,7a-six hydrogen-5H-indenes-5-ketone]
-spiral shell [(4S, 5S)-4-(benzoyloxy)-3-methoxyl group-2-cyclopentenes-1-ketone-5:3 (2S)-2-chloro-3aS, 7aS-((2,3)-1-crassitude)-6,7-dimethoxy-1,2,3,3a, 4,7a-six hydrogen-5H-indenes-5-ketone]
-spiral shell [(4S, 5S)-4-hydroxyl-pentamethylene-1-ketone-5:3 (2S)-2-chloro-3aS, 7aS-((2,3)-1-crassitude)-6,7-dimethoxy-1,2,3,3a, 4,7a-six hydrogen-5H-indenes-5-phenol]
-spiral shell [(4S, 5S)-4-hydroxyl-3-methoxyl group-2-cyclopentenes-1-ketone-5:3 (2S)-3aS, 7aS-((2,3)-1-crassitude)-6,7-dimethoxy-1,2,3,3a, 4,7a-six hydrogen-5H-indenes-5-ketone]
-spiral shell [(4R, 5S)-4-hydroxyl-3-methoxyl group-2-cyclopentenes-1-ketone-5:3 (2S)-2-chloro-3aS, 7aS-((2,3)-1-crassitude)-6,7-dimethoxy-1,2,3,3a, 4,7a-six hydrogen-5H-indenes-5-ketone]
-spiral shell [(4S, 5S)-4-(benzoyloxy)-3-methoxyl group-2-cyclopentenes-1-ketone-5:3 (2S)-2-chloro-3aS, 7aS-((2,3)-1-benzoyl tetramethyleneimine)-6,7-dimethoxy-1,2,3,3a, 4,7a-six hydrogen-5H-indenes-5-ketone]
-spiral shell [(4S, 5S)-4-ethanoyl-pentamethylene-1-ketone-5:3 (2S)-2-chloro-3aS, 7aS-((2,3)-1-crassitude)-6,7-dimethoxy-1,2,3,3a, 4,7a-six hydrogen-5H-indenes-5-ketone]
-spiral shell [(4S, 5S)-4-hydroxyl-3-methoxyl group-2-cyclopentenes-1-ketone-5:3 (2S)-2-chloro-3aS, 7aS-((2,3)-1H-tetramethyleneimine)-6,7-dimethoxy-1,2,3,3a, 4,7a-six hydrogen-5H-indenes-5-ketone] (N-Noracutumine)
-spiral shell [(4R, 5S)-4-hydroxyl-3-methoxyl group-2-cyclopentenes-1-ketone-5:3 (2S)-2-chloro-3aS, 7aS-((2,3)-1H-tetramethyleneimine)-6,7-dimethoxy-1,2,3,3a, 4,7a-six hydrogen-5H-indenes-5-ketone]
-spiral shell [(5S)-and 2-methoxyl group-2-cyclopentenes-1-ketone-5:3-3aS, 7aS-((2,3)-1H-tetramethyleneimine)-6,7-dimethoxy-1,2,3,3a, 4,7a-six hydrogen-5H-indenes-5-ketone]
-spiral shell [(5S)-and 2-methoxyl group-2-cyclopentenes-1-ketone-5:3-2-chloro-3aS, 7aS-((2,3)-1H-tetramethyleneimine)-6,7-dimethoxy-1,2,3,3a, 4,7a-six hydrogen-5H-indenes-5-ketone], be understood that:
" alkyl " expression contains the alkyl of 1 to 6 carbon atom, and it can be a straight or branched,
-" alkoxyl group " expression contains the alkoxyl group of 1 to 6 carbon atom, and it can be a straight or branched,
-" aryloxy " expression aryl moiety is wherein represented the aryloxy of phenyl or naphthyl,
-" aroyl " expression aryl moiety is wherein represented the aryl carbonyl of phenyl or naphthyl,
Its enantiomorph and diastereomer and with the additive salt of pharmaceutically acceptable acid or alkali.
According to formula (I) compound, its enantiomorph and the diastereomer of claim 1 and with the additive salt of pharmaceutically acceptable acid or alkali, wherein R on the one hand 1And R 2And R on the other hand 8And R 9Constitute other key together.
According to formula (I) compound, its enantiomorph and the diastereomer of claim 1 and with the additive salt of pharmaceutically acceptable acid or alkali, wherein R 3, R 7And R 10Representation methoxy separately.
According to formula (I) compound, its enantiomorph and the diastereomer of claim 1 and with the additive salt of pharmaceutically acceptable acid or alkali, wherein R 4Representation hydroxy, acetoxyl group or benzoyloxy.
According to formula (I) compound, its enantiomorph and the diastereomer of claim 1 and with the additive salt of pharmaceutically acceptable acid or alkali, wherein R 5Represent the chlorine atom.
According to formula (I) compound, its enantiomorph and the diastereomer of claim 1 and with the additive salt of pharmaceutically acceptable acid or alkali, wherein R 6Represent methylidene or ethyl.
According to formula (I) compound, its enantiomorph and the diastereomer of claim 1 and with the additive salt of pharmaceutically acceptable acid or alkali, wherein R 6Represent hydrogen atom.
According to formula (I) compound, its enantiomorph and the diastereomer of claim 1 and with the additive salt of pharmaceutically acceptable acid or alkali, wherein R 11And R 12Constitute the oxo base together.
According to formula (I) compound, its enantiomorph and the diastereomer of claim 1 and with the additive salt of pharmaceutically acceptable acid or alkali, wherein R 13And R 14Represent hydrogen atom separately.
10. according to formula (I) compound of claim 1, have suc as formula the configuration shown in (I '):
Figure C038191260005C1
Its enantiomorph and diastereomer and with the additive salt of pharmaceutically acceptable acid or alkali.
11. formula (I) compound according to claim 1; its enantiomorph and with the additive salt of pharmaceutically acceptable acid or alkali; these compounds are spiral shell [(4S; 5S)-4-(ethoxycarbonyl)-3-methoxyl group-2-cyclopentenes-1-ketone-5:3 (2S)-2-chloro-3aS; 7aS-((2; 3)-and the 1-crassitude)-6; 7-dimethoxy-1; 2; 3; 3a; 4; 7a-six hydrogen-5H-indenes-5-ketone]; spiral shell [(4S; 5S)-4-hydroxyl-3-methoxyl group-2-cyclopentenes-1-ketone-5:3 (2S)-2-chloro-3aS; 7aS-((2; 3)-and the 1-ethyl pyrrolidine)-6; 7-dimethoxy-1; 2; 3,3a, 4; 7a-six hydrogen-5H-indenes-5-ketone]; spiral shell [(4S; 5S)-and 4-(ethoxycarbonyl)-3-methoxyl group-2-cyclopentenes-1-ketone-5:3 (2S)-2-chloro-3aS, 7aS-((2,3)-1-propionyl tetramethyleneimine)-6; 7-dimethoxy-1; 2,3,3a; 4; 7a-six hydrogen-5H-indenes-5-ketone]; spiral shell [(4S, 5S)-4-hydroxyl-3-methoxyl group-2-cyclopentenes-1-ketone-5:3 (2S)-2-chloro-3aS, 7aS-((2; 3)-and the 1-crassitude)-6; 7-dimethoxy-1,2,3; 3a; 4,7a-six hydrogen-5H-indenes-5-ketoxime]; spiral shell [(4S, 5S)-3; 4-dimethoxy-2-cyclopentenes-1-ketone-5:3 (2S)-2-chloro-3aS; 7aS-((2,3)-1-crassitude)-6,7-dimethoxy-1; 2; 3,3a, 4; 7a-six hydrogen-5H-indenes-5-ketone]; spiral shell [(4R; 5S)-and 4-hydroxyl-3-methoxyl group-2-cyclopentenes-1-ketone-5:3 (2S)-2-chloro-3aS, 7aS-((2,3)-1-crassitude)-6; 7-dimethoxy-2; 3,3a, 7a-tetrahydrochysene-4H; 5H-indenes-4; 5-diketone]; spiral shell [(5S)-and 3-methoxyl group-2-cyclopentenes-1-ketone-5:3 (2S)-2-chloro-3aS, 7aS-((2,3)-1-crassitude)-6; 7-dimethoxy-1; 2,3,3a; 4; 7a-six hydrogen-5H-indenes-5-ketone]; spiral shell [(4S, 5S)-4-hydroxyl-2-cyclopentenes-1-ketone-5:3 (2S)-2-chloro-3aS, 7aS-((2; 3)-and the 1-crassitude)-6; 7-dimethoxy-1,2,3; 3a; 4,7a-six hydrogen-5H-indenes-5-phenol]; spiral shell [(4R, 5S)-4-hydroxyl-3-methoxyl group-2-cyclopentenes-1-ketone-5:3 (2S)-2; 4-two chloro-3aS; 7aS-((2,3)-1-crassitude)-7-methoxyl group-8-thia dicyclo [2.2.1]-1,2; 3; 3a, 4,7a-six hydrogen-5H; 6H-indenes-5, the 6-diketone].
12. preparation, is characterized in that use formula (II) compound is as raw material according to the method for formula (I) compound of claim 1:
Figure C038191260006C1
Formula (II) compound successively with demethylation agent and alkylating agent effect, obtain the special case of formula (I/a) compound-Shi (I) compound:
Figure C038191260006C2
R ' wherein 3And R ' 10Representation alkoxy separately, R 7As defined in claim 1,
Formula (I/a) compound can be in reducing medium and R wherein 15Represent the formula R of alkyl 15The compound effects of CHO obtains the special case of formula (I/b) compound-Shi (I) compound:
Figure C038191260007C1
R ' wherein 3, R 7And R ' 10As defined in claim 1, R ' 6Represent alkyl,
Formula (II), (I/a) or (I/b) compound can with R wherein 16Represent the formula (R of alkyl or aryl 16CO) 2The compound effects of O obtains the special case of formula (I/c) compound-Shi (I) compound:
R ' wherein 3, R 7And R ' 10As defined in claim 1, R 6As defined in claim 1,
R ' 4Representation hydroxy, alkyl-carbonyl oxygen base or aryl carbonyl oxygen base,
Perhaps formula (II), (I/a), (I/b) or (I/c) compound can with R wherein 15Represent alkyl and E to represent the formula E-R of leavings group 15Compound effects, obtain the special case of formula (I/d) compound-Shi (I) compound:
R ' wherein 3, R 6, R 7And R ' 10As defined in claim 1, R 4As defined in claim 1,
Formula (I/d) compound can with R wherein 17Represent the formula R of hydrogen atom or alkyl 17ONH 2Compound effects, obtain the special case of formula (I/e) compound-Shi (I) compound:
R ' wherein 3, R 4, R 6, R 7, R ' 10And R 17As defined in claim 1,
Perhaps formula (I/d) compound can with SOCl 2/ DMF effect obtains the special case of formula (I/f) compound-Shi (I) compound:
R ' wherein 3, R 4, R 6, R 7And R ' 10As defined in claim 1,
Perhaps formula (I/d) compound can with the reductive agent effect, obtain the special case of formula (I/g) compound-Shi (I) compound:
Figure C038191260009C2
R wherein 4, R 6, R 7And R ' 10As defined in claim 1, symbol  represents that this key can be singly-bound or two key,
Perhaps formula (I/d), (I/e), (I/f) or (I/g) compound can be in the presence of AIBN and n-Bu 3The SnH effect obtains the special case of formula (I/h) compound-Shi (I) compound:
R wherein 4, R 6And R 7As defined in claim 1, R 1, R 2, R 3, R 5, R 8, R 9, R 10, R 11, R 12, R 13And R 14As defined in claim 1,
Formula (I/a) to (I/h) compound constitutes all The compounds of this invention, they can be according to conventional separating technology purifying in addition, be converted into the additive salt of they and pharmaceutically acceptable acid or alkali if necessary, and suitable words are separated into their isomer according to conventional separating technology.
13. according to the method for claim 12, wherein said reductive agent is LiAlH 4
14. according to the method for claim 12, wherein E represents halogen atom or tosyl group.
15. pharmaceutical composition comprises at least a according to each formula (I) compound or additive salt and one or more pharmaceutically acceptable vehicle of itself and pharmaceutically acceptable acid or alkali in the claim 1 to 11.
16., be used to prepare the medicine of the treatment memory impairment relevant with brain aging and neurodegenerative disease according to the pharmaceutical composition of claim 15.
17. according to the pharmaceutical composition of claim 16, the wherein said memory impairment relevant with brain aging and neurodegenerative disease is selected from medicine dull-witted under Alzheimer, Parkinson's disease, Pick's disease, korsakoff's neurosis and frontal lobe and the cortex.
18. acutumine and/or the purposes of acutumine compound in pharmaceutical compositions, this pharmaceutical composition is used for the treatment of the memory impairment relevant with brain aging and neurodegenerative disease, and described acutumine compound is selected from spiral shell [(4S; 5S)-and 4-ethanoyl-3-methoxyl group-2-cyclopentenes-1-ketone-5:3 (2S)-2-chloro-3aS, 7aS-((2,3)-1-crassitude)-6; 7-dimethoxy-1,2,3; 3a, 4,7a-six hydrogen-5H-indenes-5-ketone]; spiral shell [(4S; 5S)-and 4-ethanoyl-3-methoxyl group-2-cyclopentenes-1-ketone-5:3 (2S)-2-chloro-3aS, 7aS-((2,3)-1-acetyl-pyrrolidine)-6; 7-dimethoxy-1,2,3; 3a, 4,7a-six hydrogen-5H-indenes-5-ketone]; spiral shell [(4S; 5S)-and 4-(benzoyloxy)-3-methoxyl group-2-cyclopentenes-1-ketone-5:3 (2S)-2-chloro-3aS, 7aS-((2,3)-1-crassitude)-6; 7-dimethoxy-1,2,3; 3a; 4,7a-six hydrogen-5H-indenes-5-ketone]; spiral shell [(4S, 5S)-4-hydroxyl-pentamethylene-1-ketone-5:3 (2S)-2-chloro-3aS; 7aS-((2; 3)-and the 1-crassitude)-6,7-dimethoxy-1,2; 3; 3a, 4,7a-six hydrogen-5H-indenes-5-phenol]; spiral shell [(4S; 5S)-4-hydroxyl-3-methoxyl group-2-cyclopentenes-1-ketone-5:3 (2S)-3aS; 7aS-((2,3)-1-crassitude)-6,7-dimethoxy-1; 2; 3,3a, 4; 7a-six hydrogen-5H-indenes-5-ketone]; spiral shell [(4R; 5S)-and 4-hydroxyl-3-methoxyl group-2-cyclopentenes-1-ketone-5:3 (2S)-2-chloro-3aS, 7aS-((2,3)-1-crassitude)-6; 7-dimethoxy-1; 2,3,3a; 4; 7a-six hydrogen-5H-indenes-5-ketone]; spiral shell [(4S, 5S)-4-(benzoyloxy)-3-methoxyl group-2-cyclopentenes-1-ketone-5:3 (2S)-2-chloro-3aS, 7aS-((2; 3)-and 1-benzoyl tetramethyleneimine)-6; 7-dimethoxy-1,2,3; 3a; 4,7a-six hydrogen-5H-indenes-5-ketone]; spiral shell [(4S, 5S)-4-ethanoyl-pentamethylene-1-ketone-5:3 (2S)-2-chloro-3aS; 7aS-((2; 3)-and the 1-crassitude)-6,7-dimethoxy-1,2; 3; 3a, 4,7a-six hydrogen-5H-indenes-5-ketone]; spiral shell [(4S; 5S)-4-hydroxyl-3-methoxyl group-2-cyclopentenes-1-ketone-5:3 (2S)-2-chloro-3aS; 7aS-((2,3)-1H-tetramethyleneimine)-6,7-dimethoxy-1; 2; 3,3a, 4; 7a-six hydrogen-5H-indenes-5-ketone] (N-Noracutumine); spiral shell [(4R; 5S)-and 4-hydroxyl-3-methoxyl group-2-cyclopentenes-1-ketone-5:3 (2S)-2-chloro-3aS, 7aS-((2,3)-1H-tetramethyleneimine)-6; 7-dimethoxy-1; 2,3,3a; 4; 7a-six hydrogen-5H-indenes-5-ketone]; spiral shell [(5S)-and 2-methoxyl group-2-cyclopentenes-1-ketone-5:3-3aS, 7aS-((2,3)-1H-tetramethyleneimine)-6; 7-dimethoxy-1; 2,3,3a; 4; 7a-six hydrogen-5H-indenes-5-ketone] or spiral shell [(5S)-and 2-methoxyl group-2-cyclopentenes-1-ketone-5:3-2-chloro-3aS, 7aS-((2,3)-1H-tetramethyleneimine)-6; 7-dimethoxy-1; 2,3,3a; 4,7a-six hydrogen-5H-indenes-5-ketone].
19. according to the purposes of claim 18, the wherein said memory impairment relevant with brain aging and neurodegenerative disease is selected under Alzheimer, Parkinson's disease, Pick's disease, korsakoff's neurosis and frontal lobe and the cortex dull-witted.
20. according to the purposes of acutumine in pharmaceutical compositions of claim 18, this pharmaceutical composition is used for the treatment of the memory impairment relevant with brain aging and neurodegenerative disease.
21. according to the purposes of claim 20, the wherein said memory impairment relevant with brain aging and neurodegenerative disease is selected under Alzheimer, Parkinson's disease, Pick's disease, korsakoff's neurosis and frontal lobe and the cortex dull-witted.
22. according to the purposes of acutumine compound in pharmaceutical compositions of claim 18, this pharmaceutical composition is used for the treatment of the memory impairment relevant with brain aging and neurodegenerative disease.
23. according to the purposes of claim 22, the wherein said memory impairment relevant with brain aging and neurodegenerative disease is selected under Alzheimer, Parkinson's disease, Pick's disease, korsakoff's neurosis and frontal lobe and the cortex dull-witted.
24. pharmaceutical composition comprises acutumine or acutumine compound and one or more pharmaceutically acceptable vehicle, this pharmaceutical composition is used for the treatment of the memory impairment relevant with brain aging and neurodegenerative disease; described acutumine compound be selected from spiral shell [(4S, 5S)-4-ethanoyl-3-methoxyl group-2-cyclopentenes-1-ketone-5:3 (2S)-2-chloro-3aS, 7aS-((2; 3)-and the 1-crassitude)-6,7-dimethoxy-1,2; 3,3a, 4; 7a-six hydrogen-5H-indenes-5-ketone]; spiral shell [(4S, 5S)-4-ethanoyl-3-methoxyl group-2-cyclopentenes-1-ketone-5:3 (2S)-2-chloro-3aS, 7aS-((2; 3)-and the 1-acetyl-pyrrolidine)-6,7-dimethoxy-1,2; 3,3a, 4; 7a-six hydrogen-5H-indenes-5-ketone]; spiral shell [(4S, 5S)-4-(benzoyloxy)-3-methoxyl group-2-cyclopentenes-1-ketone-5:3 (2S)-2-chloro-3aS, 7aS-((2; 3)-and the 1-crassitude)-6,7-dimethoxy-1,2; 3,3a, 4; 7a-six hydrogen-5H-indenes-5-ketone]; spiral shell [(4S; 5S)-and 4-hydroxyl-pentamethylene-1-ketone-5:3 (2S)-2-chloro-3aS, 7aS-((2,3)-1-crassitude)-6; 7-dimethoxy-1; 2,3,3a; 4; 7a-six hydrogen-5H-indenes-5-phenol]; spiral shell [(4S, 5S)-4-hydroxyl-3-methoxyl group-2-cyclopentenes-1-ketone-5:3 (2S)-3aS, 7aS-((2; 3)-and the 1-crassitude)-6; 7-dimethoxy-1,2,3; 3a; 4,7a-six hydrogen-5H-indenes-5-ketone]; spiral shell [(4R, 5S)-4-hydroxyl-3-methoxyl group-2-cyclopentenes-1-ketone-5:3 (2S)-2-chloro-3aS; 7aS-((2; 3)-and the 1-crassitude)-6,7-dimethoxy-1,2; 3; 3a, 4,7a-six hydrogen-5H-indenes-5-ketone]; spiral shell [(4S; 5S)-4-(benzoyloxy)-3-methoxyl group-2-cyclopentenes-1-ketone-5:3 (2S)-2-chloro-3aS; 7aS-((2,3)-1-benzoyl tetramethyleneimine)-6,7-dimethoxy-1; 2; 3,3a, 4; 7a-six hydrogen-5H-indenes-5-ketone]; spiral shell [(4S; 5S)-and 4-ethanoyl-pentamethylene-1-ketone-5:3 (2S)-2-chloro-3aS, 7aS-((2,3)-1-crassitude)-6; 7-dimethoxy-1; 2,3,3a; 4; 7a-six hydrogen-5H-indenes-5-ketone]; spiral shell [(4S, 5S)-4-hydroxyl-3-methoxyl group-2-cyclopentenes-1-ketone-5:3 (2S)-2-chloro-3aS, 7aS-((2; 3)-and the 1H-tetramethyleneimine)-6; 7-dimethoxy-1,2,3; 3a; 4,7a-six hydrogen-5H-indenes-5-ketone] (N-Noracutumine); spiral shell [(4R, 5S)-4-hydroxyl-3-methoxyl group-2-cyclopentenes-1-ketone-5:3 (2S)-2-chloro-3aS; 7aS-((2; 3)-and the 1H-tetramethyleneimine)-6,7-dimethoxy-1,2; 3; 3a, 4,7a-six hydrogen-5H-indenes-5-ketone]; spiral shell [(5S)-2-methoxyl group-2-cyclopentenes-1-ketone-5:3-3aS; 7aS-((2; 3)-and the 1H-tetramethyleneimine)-6,7-dimethoxy-1,2; 3; 3a, 4,7a-six hydrogen-5H-indenes-5-ketone] or spiral shell [(5S)-2-methoxyl group-2-cyclopentenes-1-ketone-5:3-2-chloro-3aS; 7aS-((2; 3)-and the 1H-tetramethyleneimine)-6,7-dimethoxy-1,2; 3; 3a, 4,7a-six hydrogen-5H-indenes-5-ketone].
25. according to the pharmaceutical composition of claim 24, the wherein said memory impairment relevant with brain aging and neurodegenerative disease is selected under Alzheimer, Parkinson's disease, Pick's disease, korsakoff's neurosis and frontal lobe and the cortex dull-witted.
CNB038191261A 2002-06-25 2003-06-16 Tetrandrine and Tetrandine Compounds, Synthesis and Uses Expired - Fee Related CN1303069C (en)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
CNA021214794A CN1465566A (en) 2002-06-25 2002-06-25 Tetrandrine and Tetrandine Compounds, Synthesis and Uses
CN02121479.4 2002-06-25
PCT/IB2003/002600 WO2004000815A1 (en) 2002-06-25 2003-06-16 Acutumine and acutumine compounds, synthesis and use

Publications (2)

Publication Number Publication Date
CN1675183A CN1675183A (en) 2005-09-28
CN1303069C true CN1303069C (en) 2007-03-07

Family

ID=29742994

Family Applications (2)

Application Number Title Priority Date Filing Date
CNA021214794A Pending CN1465566A (en) 2002-06-25 2002-06-25 Tetrandrine and Tetrandine Compounds, Synthesis and Uses
CNB038191261A Expired - Fee Related CN1303069C (en) 2002-06-25 2003-06-16 Tetrandrine and Tetrandine Compounds, Synthesis and Uses

Family Applications Before (1)

Application Number Title Priority Date Filing Date
CNA021214794A Pending CN1465566A (en) 2002-06-25 2002-06-25 Tetrandrine and Tetrandine Compounds, Synthesis and Uses

Country Status (19)

Country Link
US (1) US20060167076A1 (en)
EP (1) EP1608625A1 (en)
JP (1) JP2006501174A (en)
KR (1) KR100677018B1 (en)
CN (2) CN1465566A (en)
AR (1) AR040462A1 (en)
AU (1) AU2003242278A1 (en)
BR (1) BR0312444A (en)
CA (1) CA2491214A1 (en)
EA (1) EA007229B1 (en)
GE (1) GEP20074178B (en)
MA (1) MA27264A1 (en)
MX (1) MXPA05000076A (en)
NO (1) NO20050214L (en)
NZ (1) NZ537405A (en)
PL (1) PL374039A1 (en)
UA (1) UA80555C2 (en)
WO (1) WO2004000815A1 (en)
ZA (1) ZA200410280B (en)

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2476682B1 (en) * 2009-09-09 2017-04-26 Sumitomo Dainippon Pharma Co., Ltd. 8-oxodihydropurine derivative
AU2014101153A4 (en) * 2014-01-03 2014-10-23 Macau University Of Science And Technology A Group of Alkaloids, the Novel Autophagic Enhancers for Treatment of Cancers and Neurodegenerative Conditions Thereof

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4749707A (en) * 1984-02-29 1988-06-07 Covex, S.A. Citric acid salt of (+) vinpocetine
CN1052225A (en) * 1990-02-07 1991-06-12 福建省仙游电机厂 A kind of automobile current generator of big specific power and manufacture method thereof
CN1220260A (en) * 1997-12-19 1999-06-23 中国科学院上海药物研究所 Acorus calamus extracts in Acorus gramineus and their use

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4749707A (en) * 1984-02-29 1988-06-07 Covex, S.A. Citric acid salt of (+) vinpocetine
CN1052225A (en) * 1990-02-07 1991-06-12 福建省仙游电机厂 A kind of automobile current generator of big specific power and manufacture method thereof
CN1220260A (en) * 1997-12-19 1999-06-23 中国科学院上海药物研究所 Acorus calamus extracts in Acorus gramineus and their use

Also Published As

Publication number Publication date
KR100677018B1 (en) 2007-01-31
NZ537405A (en) 2006-03-31
CA2491214A1 (en) 2003-12-31
KR20050058999A (en) 2005-06-17
MXPA05000076A (en) 2005-04-08
WO2004000815A1 (en) 2003-12-31
NO20050214L (en) 2005-01-13
EA007229B1 (en) 2006-08-25
PL374039A1 (en) 2005-09-19
UA80555C2 (en) 2007-10-10
EA200500081A1 (en) 2005-06-30
BR0312444A (en) 2005-05-10
AU2003242278A1 (en) 2004-01-06
CN1465566A (en) 2004-01-07
GEP20074178B (en) 2007-08-10
US20060167076A1 (en) 2006-07-27
HK1077823A1 (en) 2006-02-24
AR040462A1 (en) 2005-04-06
CN1675183A (en) 2005-09-28
ZA200410280B (en) 2006-07-26
JP2006501174A (en) 2006-01-12
MA27264A1 (en) 2005-03-01
EP1608625A1 (en) 2005-12-28

Similar Documents

Publication Publication Date Title
CN1037439C (en) Neuroprotective indolone and related derivatives
CN1028104C (en) Carbostyril derivatives
CN1720232A (en) Sinomenine and sinomenine compound, synthetic and application
CN1029960C (en) Process for preparing chromanol derivatives having neuroprotective effect
CN1882541A (en) N-[phenyl(alkyl-2-piperidinyl)methyl]benzamide derivatives, their preparation and therapeutic use
CN1649845A (en) Muscarinic antagonists
CN1061035C (en) Phenylalkanolamine derivatives
CN1105360A (en) 1-[2H-1-Benzopyran-2-on-8-yl]-piperazine derivatives
CN1756757A (en) Pyrroloimidazole derivatives, their preparation, pharmaceutical composition containing them, and their use as nootropic agents
CN1242366A (en) Diaza-spiro [3,5] nonane derivatives
CN1293195A (en) New polycyclicazaindole compound, its preparation method are medicine composition containing same
CN1303069C (en) Tetrandrine and Tetrandine Compounds, Synthesis and Uses
CN1126739C (en) Novel substituted tetrahydropyridin derivatives, method of preparation and pharmaceutical compositions containing them
CN1956962A (en) Tetrahydroisoquinoline sulfonamide derivatives, processes for their preparation and their use in therapy
CN1046726C (en) Imidazopyridine-pyrrolidone, its preparation method and medicinal use
CN1486321A (en) Indole Derivatives and Their Medical Applications
CN1158257C (en) Novel amino pyrroline compound, its prepn. method and pharmaceutical compositions contg. same
CN1206221C (en) Acridine derivatives
CN1262680A (en) 6-pyrrolidin-2-ylpyrindine derivatives, their preparation and application in therapy
HK1077823B (en) Acutumine and acutumine compounds, synthesis and use
CN1342152A (en) N-substituted imide derivatives with serotonergic activity
HK1060126A (en) Acutumine and acutumine compounds, synthesis and use
CN1142913C (en) Tetrahydroisoquinoline alkanol derivatives and pharmaceutical compositions thereof
CN1466573A (en) 5-phenylbenzylamine compound, its preparation method and its synthetic intermediate
CN1041156A (en) Strengthen the different  azoles of tetrahydrochysene and the azepine  derivative of brain function

Legal Events

Date Code Title Description
C06 Publication
PB01 Publication
C10 Entry into substantive examination
SE01 Entry into force of request for substantive examination
REG Reference to a national code

Ref country code: HK

Ref legal event code: DE

Ref document number: 1077823

Country of ref document: HK

C14 Grant of patent or utility model
GR01 Patent grant
C19 Lapse of patent right due to non-payment of the annual fee
CF01 Termination of patent right due to non-payment of annual fee